Short and Easily Scalable Synthesis of the Sex Pheromone of the Horse-Chestnut Leaf Miner (Cameraria ohridella) Relying on a Key Ligand- And Additive-Free Iron-Catalyzed Cross-Coupling

Article abstract of DOI:10.1021/acs.oprd.0c00191

We describe in this work a short six-step convergent high-scale synthesis of the sex pheromone of the horse-chestnut leaf miner ((8E,10Z)-tetradeca-8,10-dienal). This procedure relies on a key stereoselective iron-catalyzed Kumada cross-coupling, which affords the coupling product in high yield in the absence of additional ligands or additives. DFT calculations moreover suggest that ω-alkoxide groups on iron-ligated chains in transient organoiron(II) intermediates can enhance their stability and hamper their decomposition in off-cycle β-hydride elimination reactions.

Full text of DOI:10.1021/acs.oprd.0c00191

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Communication
Short and easily scalable synthesis of the sex pheromone of
the horse-chestnut leaf miner (Cameraria ohridella) relying on
a key ligand- and additive-free iron-catalyzed cross-coupling.
Pablo Chourreu, Olivier Guerret, Loic Guillonneau, Eric Gayon, and Guillaume P. Lefèvre
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00191 • Publication Date (Web): 18 Jun 2020
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Organic Process Research & Development
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Short and easily scalable synthesis of the sex pheromone of the horse-
chestnut leaf miner (Cameraria ohridella) relying on a key ligand-
and additive-free iron-catalyzed cross-coupling.
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Pablo Chourreu,a,b Olivier Guerret,b Loïc Guillonneau,b Eric Gayon,*b and Guillaume Lefèvre*a
a Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, CSB2D, 75005 Paris,
France; b M2i Development, Bâtiment ChemStart’Up, Allée Le Corbusier, 64170 Lacq, France.
Supporting Information Placeholder
ABSTRACT: We describe in this work a short 6-step convergent high-scale synthesis of the sex pheromone of the horse-chestnut
leaf miner (8E,10Z-tetradeca-8,10-dienal). This procedure relies on a key stereoselective iron-catalyzed Kumada cross-coupling,
which affords the coupling product with a high yield in the absence of additional ligands or additives. DFT calculations moreover
suggest that ω-alkoxide groups on iron-ligated chains in transient organoiron(II) intermediates can enhance their stability and hamper
their decomposition in off-cycle β-hydride elimination reactions.
Keywords: pheromones, cross-coupling, iron catalysis, mechanisms
INTRODUCTION
Scheme 1. Structure of the sex pheromone of the horse-
Unlike the use of pesticides, which currently causes
significant ecological issues, bio-control based on use of
pheromones is an eco-friendly solution for the protection of a
wide range of crops, vineyards, and plants.1a Moreover,
pheromones are fully biodegradable, specific to the sole target
species, and do not display toxicity to human health.1b In our
efforts to develop efficient and reliable high-scale synthetic
procedures to access a large variety of chemicals of interest for
biological control, we report herein a new convergent synthesis
of the sex pheromone of horse-chestnut leaf miner (Cameraria
ohridella, 8E,10Z-tetradeca-8,10-dienal, 1, Scheme 1).
Significant damage is caused by this leaf-mining moth to horse
chestnut trees in almost all countries of western Europe,
especially during late summer time. During this period, larvae
cause necrosis of the leaves, following by their shedding. In that
context, protection of the trees can be achieved by an efficient
control of the horse-chestnut leaf miner infestations by using
the specific sex pheromone 1. This pheromone attracts, traps or
sexually confuses males, interrupting the reproductive cycle of
the leaf-miner.2
chestnut leaf miner (1) and reported synthetic strategies.
Csp-Csp2 Sonogashira (Svatos, 1999) or Kumada
(Grodner, 2009) coupling and alkyne reduction
10
8
6
4
2
O
11
1
9
7
5
3
H
12
13
This work : Csp3-Csp2 Fe-catalyzed
cross-coupling; 6 steps, 40% yield
14
(Francke, 2002)
Wittig
tetrahydropyranylether onto pentanal. The corresponding 1,3-
enyne is obtained after dehydration at 155-165 °C under
reduced pressure (40% yield, 10Z/10E = 81/19), and a reduction
of the triple bond by LiAlH4 at high temperature affords the
expected diene (71% yield, 10Z/10E = 67/33). A last method
described by Francke in 2002 relies on the construction of the
C10─C11 linkage by a Wittig reaction involving an α,β-
unsaturated aldehyde.4 In that last example, the C9─C10 bond
comes from the 2-propyne-1-ol used as a starting reagent.
Therefore, all syntheses for pheromone 1 so far reported involve
important step numbers and are for some of them linear
procedures involving numerous steps with a low atom economy
and expensive Pd-based catalysts. Moreover, they all rely on
key acetylenic intermediates, which thus requires to handle
highly reactive or volatile alkyne sources (such as lithium
acetylide2,3) to introduce and functionalize those species. This
Several syntheses of 1 were reported in the past, relying
mostly on the introduction of either C9─C10 or C10─C11 linkages
as key steps (Scheme 1). Syntheses reported by Svatos2 (7 steps,
28% yield) and Grodner3 (9 steps, 12% yield) relied on the
introduction of the C9─C10 bond respectively by Sonogashira
and Kumada cross-couplings between alkenyl iodides and pent-
1-yne or its Grignard. An 1,3-enyne is then obtained, and further
reduction of the triple bond by dicyclohexylborane affords the
expected conjugated diene. Grodner also reported an alternative
strategy, relying on the introduction of the C9─C10 linkage by
addition of the lithium acetylide salt of nonyn-8-ol
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Organic Process Research & Development
hampers application of these syntheses at high scales, making
Page 2 of 7
4 was obtained with a good 87 % yield. Preparation of α,ω-
magnesium alkoxide salt of Grignard reagent 5 was then
performed from 4 according to our previously reported
procedure.5 Addition of 4 onto a THF mixture containing in-
situ-synthesized n-BuMgCl (1.0 equiv.) and Mg (1.1 equiv.) at
-10 °C led to formation of the corresponding magnesium
alkoxide salt. Progressive heating at 70 °C allowed formation
of the corresponding Grignard reagent 5 with an overall 90 %
yield. 5 was then directly subjected to react with (1E,3Z)-dienol
phosphate 6a in a one-pot strategy. Synthesis and purification
of 6a is discussed in the following section.
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them unattractive for industrial eco-friendly purposes.
Inspired by our previous work5 on the synthesis of a similar
dienic pheromone (sex pheromone of the European grapevine
moth Lobesia botrana), we report herein a synthesis of
pheromone 1 relying on the introduction of the C7─C8 linkage
by a key alkyl-alkenyl Fe-catalyzed Kumada cross-coupling
between a Grignard reagent and a dienol phosphate. This
synthesis is a 6-step convergent procedure starting from the
diethyl ester of pimelic acid (EtOOC-(CH2)5-COOEt) and
trans-hept-2-enal, which affords pheromone 1 with a 40 % yield
and a diastereomeric purity of 90 %. This method is moreover
easily scalable, and allowed to prepare ca. 40 g of 1, and the use
of a cheap, eco-friendly and abundant transition metal such as
iron as a catalyst of the key cross-coupling step is an appealing
alternative to the use of noble metals.6 The synthetic strategy
followed in this work is discussed thereafter. The reactivity of
the organometallic species formed during the iron-catalyzed
cross-coupling step is also discussed by means of DFT
calculations in order to rationalize the selectivity of the coupling
process.
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Preparation of (1E,3Z)-dienol phosphate 6a. Stereoselective
preparation of dienol phosphates was described by Cahiez in
2008 starting from α,β-unsaturated aldehydes.8 Dienol
phosphate 6a was prepared by treatment of trans-hept-2-enal 8
with tBuOK at -45 °C (Scheme 3), followed by addition of
diethyl chlorophosphate. A mixture of (1E,3Z) and (1E,3E)-
dienol phosphates 6a and 6b (80 % yield, 70/30 ratio) was
obtained.
Scheme 3. Preparation of diastereomerically pure (1E,3Z)-
dienol phosphate 6a.
RESULTS AND DISCUSSION
The synthetic strategy followed in this work is detailed in
Scheme 2. This has been inspired by our previous work on
synthesis of the sex pheromone of Lobesia botrana: we could
indeed demonstrate that α,ω-magnesium alkoxide salts of
Grignard reagents could be used as efficient nucleophiles in
ligand- and additive-free iron-catalyzed cross-couplings with
alkenyl electrophiles.5 Applying this strategy to the convergent
synthesis of 1, the Grignard reagent of 7-magnesium alkoxide
salt 5 is subjected to an iron-catalyzed Kumada cross-coupling
with diastereomerically pure (1E,3Z)-dienol phosphate 6a.
Preparation of synthons 5 and 6a as well as the cross-coupling
step are detailed thereafter.
1) t-BuOK (1.2 equiv.)
THF/NMP, -45°C, 0.5 h
OP(O)(OEt)2
O
2) ClP(O)(OEt)2 (1.1 equiv.)
-45°C
8
6a
6b
(1E,3E)
(1E,3Z) and
(80%, 1E,3Z/1E,3E = 70/30)
O
O
O
OP(O)(OEt)2
(1.0 equiv.)
6a
(1E,3Z)
MeC6H11, 70°C to 20°C
68% for this step
(54% overall, 1E,3Z/1E,3E = 100/0)
Preparation of the C1─C7 synthon (5). Diethyl pimelate 2 was
chosen as a starting material for the construction of the C1─C7
chain (Scheme 2). Reduction of the diester 2 into the
corresponding diol 3 (heptane-1,7-diol) was achieved using 3.0
equiv. of sodium bis(2-methoxyethoxy)aluminium hydride
(Red-Al) in an almost quantitative yield (98%). Monochloration
of 3 leading to 7-chloroheptan-1-ol 4 was then performed using
aqueous HCl (37 wt-%) as a chlorinating reagent in toluene
(reflux conditions, 20 h), adapting procedure reported by Chong
for monobromination of α,ω-diols.7 During this step, formation
of 1,7-dichloroheptane could be limited by carrying the
chlorination at low diol concentrations (0.15 M in toluene), and
Scheme 2. Synthesis route toward pheromone 1 described in this work.
Red-Al
(70 wt-%, 3.0 equiv.)
2-MeTHF, 45 °C
OEt
O
O
HO
OH
EtO
3
(98%)
2
Mg (2 equiv.)
THF, 70 °C
+ Mg
BuCl
BuMgCl
MgCl
HCl
(37 wt-%, 50.0 equiv.)
ClMgO
HO
Cl
Toluene, 110 °C, 20 h
THF, -10 °C
to 70 °C
5
(90%)
4
(87%)
OP(O)(OEt)2
TEMPO (10 mol %)
ACN, 20 °C, 0.5 h;
2
8
10
O
6a
(1E,3Z : 1E,3E = 100 : 0)
14
HO
1
1
(82%, 8E,10Z = 90%)
then PhI(OAc)2 (1.1 equiv.)
10 °C to 20 °C
Fe(acac)3 (0.1 mol %)
THF, -5 °C to 20 °C
7
(89%, 8E,10Z > 95%)
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Organic Process Research & Development
Separation of 6a/6b mixture by chromatography on silica gel is
Scheme 4. Structures of tris- (a) and tetra-coordinated (b)
isomers of A (spin multiplicities superscripted and DFT-
computed energies in parenthesis (kcal.mol-1, PBE0-D3 /
PCM THF level)); Mg = Mg(OMe2)2.
1
2
3
4
5
6
7
8
not easily carried out at high industrial scales. In order to
circumvent this matter, (1E,3Z)-dienol phosphate 6a and its
minor isomer (1E,3E) (6b) were conveniently separated by
treating the 6a/6b mixture with 1.0 equiv. of maleic anhydride
in methylcyclohexane. A Diels-Alder reaction selectively
occurs between 6b and maleic anhydride, leading to the
corresponding cycloaddition product.9 Precipitation of the latter
allowed an easy purification of 6a, obtained with an overall
54% yield from 8 and an excellent diastereomeric ratio
(1E,3Z)/(1E,3E) = 100/0. Diastereomerically pure 6a was then
subjected to cross-coupling with 5 in an iron-catalyzed Kumada
cross-coupling.
OMgBr
4
a)
FeII
FeII
4
3
OMgBr
3
H
4
OMgBr
OMgBr
9
5A
R,R,R (0.0)
3AR,R,R,
H (22.9)

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BrMg
b)
BrMg
3
O
FeII
O
FeII
Iron-catalyzed cross-coupling between 5 and 6a and
obtention of pheromone 1. Cross-coupling between 5 and 6a
proceeded in one-pot conditions after obtention of ω-alkoxide
Grignard 5. Reaction medium was cooled down at -5 °C and,
after addition of Fe(acac)3 (0.001 equiv.), dienol phosphate 6a
was added dropwise. Due to the high viscosity of the bulk, the
reaction medium was stirred overnight at 20 °C to ensure full
consumption of 5. Cross-coupling product 7 was then obtained
in a high 89 % isolated yield. Moreover, this coupling is highly
stereoselective since the expected isomer (8E,10Z)-7 is
obtained with a 95 % diastereomeric purity. It is worth noting
that the alkyl-alkenyl Fe-catalyzed Kumada cross-coupling
between 5 and 6a remarkably proceeds without requiring
additional ligands10a or any toxic additive such as N-
MethylPyrrolidinone (NMP),10b-c as usually required by classic
procedures. Importantly, very small amount of Grignard β-
elimination byproduct is observed (< 5 %). Oxidation of 7 by
iodobenzene diacetate (PhI(OAc)2) in the presence of a catalytic
amount of TEMPO finally affords pheromone 1 (82 % yield)
with a 90 % diastereomeric purity.11
3
4
4
OMgBr
OMgBr
5A
3A
R,R,R,O (-10.2)
R,R,R,O (-4.4)
suggests that the transient organoiron(II) intermediates obtained
during the catalytic cycle exhibit a good kinetic stability
towards β-hydride elimination. This led us to investigate the
stability of the transmetallated species [FeII((CH2)7OMgX)3]─
(X = Br or Cl) by DFT computation.
In order to ensure a good compromise between accuracy and
computation time, complex A ([FeII((CH2)4OMgBr)2(n-Bu)]─)
was first chosen as a model for [FeII((CH2)7OMgX)3]─. A
tetrahedral environment was chosen for MgII cations (including
explicit solvation by two Me2O molecules, chosen as a model
for THF). Different isomers of A were computed, depending on
their spin multiplicity and coordination number (Scheme 4).
Tris-coordinated species 5AR,R,R (high-spin, S = 2) and 3AR,R,R,βH
(intermediate spin, S = 1) were found to be the two lowest
energetic states with a coordination sphere involving the three
σ-alkyl ligands and no chelation by ω-alkoxide moieties
(Scheme 4a).
Overall, this procedure allows to achieve synthesis of
pheromone 1 with a 40 % yield and a 90 % diastereomeric
purity in a short 6-step synthesis from commercial diethyl
pimelate 2 and trans-hept-2-enal 8. It is also worth mentioning
that the 6-step procedure described in this work includes the 2-
step preparation of the α,ω-chloroalcohol 4, its bromide
analogue being used as a starting material in Svatos method.2
Our procedure allowed us to prepare a batch of ca. 40 g of
pheromone 1, showing that this synthesis can easily be scaled
up and is thus particularly appealing for industrial applications.
After formulation of the pheromone, such an amount allows to
treat an area of ca 80 km2.
The high-spin configuration was the most stable one, akin to
numerous well-known ate-[R3FeII]─ species (R = Me,12a Et,12b
,
Mes,14 Ph15), lying 22.9 kcal.mol-1 under its triplet analogue.
Local FeII environment in AR,R,R,βH was square-planar,
3
featuring the three coordinating σ-hydrocarbyl ligands, as well
as an agostic interaction with one β-hydrogen. Feasibility of a
β-agostic interaction is a prerequisite for the β-hydride
elimination step. Such interaction requires the existence of
vacant d orbitals located on the metal, making possible the
interaction of the latter with bonding σ(Cβ─H) orbitals. Since
Fe-catalyzed cross-couplings between alkyl nucleophiles and
alkenyl electrophiles usually require additional ligands (e.g. N-
Heterocyclic Carbenes10a) or additives (such as NMP10b) to
proceed with high yields. The mechanistic insights of those
transformations still remain unclear, but it was recently
high-spin FeII species (S = 2) do not have vacant d orbitals, spin
crossover to an intermediate multiplicity (S = 1 in AR,R,R,βH
3
)
must thus occur prior to the β-elimination process, in agreement
with previously reports on (P,P)2FeII(Et)2 systems.16
demonstrated
that
homoleptic
tris-coordinated
ate
However, a more stable isomer of A can be obtained thanks
to a coordination of one of the ω-alkoxide moiety onto the FeII
ion, leading to a tetra-coordinated species with a high-spin
ground state (5AR,R,R,O, stabilized by 10.2 kcal.mol-1 with
respect to AR,R,R, Scheme 4b). Neither AR,R,R,O nor its triplet
analogue 3AR,R,R,O can provide the requested β-agostic bond to
initiate the β-hydride elimination process. Therefore, the
energetic span required to ensure such a β-agostic interaction
can be evaluated at 33.1 kcal.mol-1: this corresponds to the
organoiron(II) species [R3FeII]─ were formed by reduction of
precursors such as Fe(acac)3 in the presence of an excess of
alkyl Grignard reagents (RMgX, R = Me,12a Et12b). Alkyliron(II)
species can be either key intermediates in the cross-coupling
pathway, quickly lead to reduced iron polynuclear
frameworks,12 or undergo decomposition by β-hydride
elimination when the alkyl chain displays H atoms in β position
to the iron.13 The high yield obtained for cross-coupling
between 5 and 6a in the absence of additional ligand or additive
5
5
5
energy difference between quaternized species AR,R,R,O and
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3AR,R,R,βH. This energy is far too high to be efficiently overcome
in the coupling conditions (-5°C to 20°C), making unlikely the
formation of the β-agostic bond. It can thus be drawn from those
calculations that chelation of the FeII ion by ω-alkoxide moieties
in in-situ formed tris-alkyl ate species can hamper the
feasibility of β-agostic bonds. However, for ω-alkoxide
Grignard reagents with alkyl chains longer than those in model
A (such as 5 in the present work), formation of a large
metallacycle involving a FeII─O ligation might not be favored
due to the high flexibility of the former. Indeed, in the case of
5, a 9-member metallacycle is formed, and was found to be
slightly less stable than 5 by 2.2 kcal.mol-1 (5BR,R,R,O see SI). In
that case, an intermolecular ligation of a tris-coordinated ate-
FeII species by the alkoxide moiety of an additional equivalent
of 5 can occur, consistently with the beneficial effect of
magnesium alkoxide salts used as additives observed on alkyl-
alkenyl Fe-catalyzed cross-coupling, as recently reported by
some of us.17 Intra- or intermolecular stabilization of transient
iron(II) intermediates by alkoxide moieties can thus prevent the
evolution of those species toward β-hydride elimination
pathway, which can account for the good conversion of the
Grignard reagent in the cross-coupling between 5 and 6a. This
result echoes a recent report by Neidig, who demonstrated that
transmetallation of Grignard reagents bearing ω-acetal groups
onto NHC-ligated FeII species leads to an improved stability of
the alkyliron(II) intermediates toward β-hydride elimination.18
In-depth mechanistic studies are under progress in order to
understand the accurate role of the ω-magnesium alkoxide
functionalities in the cross-coupling sequence, as well as to
investigate the ability of the tris-alkyliron(II) complex
[FeII((CH2)7OMgX)3]─ to be involved as an on-cycle species in
the coupling.
and were used as received unless otherwise stated. High purity
1
2
3
4
5
6
7
8
Fe(acac)3 (>99%) from Sigma-Aldrich was used. Dry solvents were
obtained from commercial sources. All reactions were conducted
in dry flasks under argon atmosphere. Titration of Grignard
reagents was performed according to the procedure reported by
Watson19 by using a 1 M solution of sec-butyl alcohol in toluene, 1
mL of the THF solution of the Grignard reagent, and 1−2 mg of
2,2-biquinoline.
DFT calculations were carried out using the Gaussian09 v. D.01
code. Theory level: PBE0-D3 / 6-31+G* (C, H, Mg, O), 6-311G
(Br), SDD and associated pseudopotential (Fe), solvation model:
PCM-THF. See SI for the corresponding references.
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Diethyl (hepta-1,3-dien-1-yl)-phosphate ((1E,3Z)-6a and
(1E,3E)-6b mixture). In a dry four-neck 2 L round-bottom flask
equipped with a mechanical stirrer, a thermometer, and an argon
inlet were introduced, at 20°C, potassium tert-butoxide (61.7 g, 535
mmol, 1.2 eq.), THF (450 mL), and NMP (300 mL). The mixture
was stirred at -45°C using a cold finger in an ethanol bath and trans-
heptenal (50.0 g, 446 mmol, 1 eq.) was added dropwise in 30 min.
30 min after the end of the addition, diethyl chlorophosphate (85.6
g, 491 mmol, 1.1 eq.) was added dropwise in 1 h at -45°C. The
mixture was stirred for 1 h, and then quenched by adding 500 mL
of distilled water at 5°C. After 45 min under stirring at 20°C, the
aqueous layer was extracted with 3 x 250 mL of methyl tert-butyl
ether (MTBE). The combined organic layers were washed with 3 x
250 mL of distilled water and concentrated under vacuum. The
crude product was purified by chromatography on a silica gel
column using heptane/EtOAc 9:1 as eluent to afford 88.6 g (80%)
of an orange liquid (1E,3Z/1E,3E = 70/30). GC: tR(1E, 3Z) = 8.83
min, tR(1E, 3E) = 8.94 min. MS (EI) m/z: [M]+ = 248.1.
Diethyl ((1E,3Z)-hepta-1,3-dien-1-yl)-phosphate (6a). In a dry
four-neck 2 L round-bottom flask equipped with a mechanical
stirrer, a thermometer, a condenser, and an argon inlet were
introduced the mixture of isomers 6a and 6b (310 g, 1.25 mol, 1
eq., 70/30), maleic anhydride (122 g, 1.25 mol, 1 eq.) and methyl-
cyclohexane (1 L). The mixture was stirred at 70°C for 3 h then
stirred at 20°C overnight. 1 L of an aqueous solution of NaOH (3M)
was added to the reaction mixture at 40°C to reach a pH of 14. After
decantation, the aqueous layer was extracted with 2 x 600 mL of
heptane. The combined organic layers were washed with 2 x 600
mL of a saturated NaCl aqueous solution and concentrated under
vacuum. The resulting crude was dissolved in 200 mL of MTBE,
filtrated and concentrated under vacuum again to afford 210.1 g
(68%) of an orange liquid (1E,3Z/1E,3E = 100/0). GC: tR(1E, 3Z)
= 8.83 min. 1H NMR (CDCl3, 400 MHz) δ 6.67 (dd, J = 11.8, 6.1
Hz, 1H), 6.29 (t, J = 11.7 Hz, 1H), 5.86 (t, J = 11.2 Hz, 1H), 5.44
(dt, J = 10.8, 7.6 Hz, 1H), 4.21 – 4.14 (m, 4H), 2.12 – 2.06 (m, 2H),
1.43 – 1.38 (m, 2H), 1.36 (t, J = 7.1, 6H), 0.90 (t, J = 7.4 Hz, 3H).
13C NMR (CDCl3, 100 MHz) δ 139.3, 132.4, 122.3, 113.6, 64.7,
64.6, 29.9, 22.8, 16.3, 16.2, 13.9. MS (EI) m/z: [M]+ = 248.1.
In summary, we have reported a new and easily scalable
synthesis of the sex pheromone of the horse-chestnut leaf miner
(8E,10Z-tetradeca-8,10-dienal). Our strategy relies on the
introduction of the C7─C8 linkage by a key additive-free Fe-
catalyzed Kumada cross-coupling between a α,ω-magnesium
alkoxide Grignard reagent and a diastereomerically pure
(1E,3Z)-dienol phosphate. Presence of ω-alkoxide groups on
the lateral chains of the transmetallated alkyliron(II)
intermediates moreover enhances the stability of those species
toward β-hydride elimination, ensuring their good conversion
in the cross-coupling process in the absence of additional
ligands or of the usual additives.
EXPERIMENTAL SECTION
Gas chromatography analyses (GC) and mass spectra were
performed on a Hewlett-Packart HP 5973 mass spectrometer via a
GC/MS coupling with a Hewlett-Packart HP 6890 chromatograph
equipped with a capillary column HP-5MS (50 m x 0.25 mm x 0.25
µm. 5% polysilarylene / 95% polydimethylsiloxane). Ionisation
was performed by electronic impact (EI, 70 eV). Mass spectra are
reported as m/z (molecular ion peak, % of relative intensity).
Helium was used as a carrier gaz (1.0 mL/min, ratio split: 100).
Standard analysis conditions: 40°C (hold 1 min) to 250°C (hold 10
min), heating rate: 20°C/min. Standard flash column
chromatography was performed on silica gel 60.1H NMR (400
MHz, CDCl3), 13C NMR (100 MHz, CDCl3) were recorded on a
Brucker Avance III HD 400 instrument. Chemical shifts (δ) are
given in ppm from TMS (1H, 13C). Coupling constants (J) are given
in Hz. The following abbreviations are used: s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet). All reagents and solvents were
obtained from either Sigma-Aldrich, Acros, Alfa, VWR, or TCI
Heptane-1,7-diol (3). In a dry four-neck 2 L round-bottom flask
equipped with a mechanical stirrer, a thermometer, a condenser,
and an argon inlet were introduced diethyl pimelate (100 g, 462
mmol, 1 eq.) and 2-MeTHF (500 mL). The solution was stirred at
45°C and a sodium bis(2-methoxyethoxy)aluminum hydride
solution (Red-Al 70 wt-%) (400 g, 1.39 mol, 3 eq.) was added
dropwise in 2 h. The mixture was stirred for 3 h at 45°C, and then
very carefully quenched by adding dropwise 600 mL of an aqueous
solution of HCl (18%). After decantation, still at 45°C, the aqueous
layer was extracted with 3 x 150 mL of methyl-THF. The combined
organic layers were concentrated under vacuum. The resulting
mixture was purified by distillation under reduced pressure (60°C;
20 mbar) to remove methoxyethanol from Re-Al quench, and to
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obtain 60.1 g (98%) of a slightly yellow liquid. GC: tR = 6.94 min.
TEMPO (3.8 g, 24.2 mmol, 0.1 eq). The mixture was stirring for
30 min at 20°C then cooled to 10°C. Once at this temperature,
(diacetoxyiodo)benzene (85.6 g, 266 mmol, 1.1 eq.) was
progressively added then the reaction mixture was stirred for 2 h at
20°C. 250 mL of a saturated sodium thiosulfate aqueous solution
were added to quench the reaction. After decantation, the aqueous
layer was extracted with 2 x 200 mL of AcOEt. The combined
organic layers were washed with 3 x 200 mL of a saturated
NaHCO3 aqueous solution and concentrated under vacuum. The
crude product was purified by chromatography on a silica gel
column using heptane/EtOAc 9:1 as eluent to afford 41.3 g (82%)
1
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1H NMR (CDCl3, 400 MHz) δ 3.63 (t, J = 6.6 Hz, 4H), 1.58 – 1.52
(m, 4H), 1.41 – 1.31 (m, 6H).13C NMR (CDCl3, 100 MHz) δ 62.9
(2C), 32.7 (2C), 29.2 (2C), 25.7. MS (EI) m/z: [M]+ = 132.0.
7-chloroheptan-1-ol (4). In a dry four-neck 4 L round-bottom
flask equipped with a mechanical stirrer, a thermometer, a
condenser, and an argon inlet were introduced heptane-1,7-diol 3
(40 g, 302.5 mmol, 1 eq.) and toluene (1 L). The solution is
vigorously stirred and a 37% HCl aqueous solution (1.25 L, 15.13
mol, 50 eq.) is progressively added to the reaction mixture. After
stirring the reaction at 110°C for 20 h, the organic layer is separated
from the aqueous one, which is extracted with 3 x 200 mL of
toluene. The combined organic layers were washed with 2 x 200
mL of saturated NaHCO3 aqueous solution and with 200 mL of
distilled water, dried over magnesium sulphate, filtrated and
concentrated under vacuum. The resulting product was purified by
chromatography on a silica gel column using heptane/EtOAc 7:3 as
eluent to obtain 39.4 g (87%) of a slightly yellow liquid. GC: tR =
6.42 min. 1H NMR (CDCl3, 400 MHz) δ 3.65 (t, J = 6.6 Hz, 2H),
3.53 (t, J = 6.7 Hz, 2H), 1.83 – 1.72 (m, 2H), 1.62 – 1.53 (m, 2H),
1.49 – 1.41 (m, 2H), 1.41 – 1.33 (m, 4H). 13C NMR (CDCl3, 100
MHz) δ 63.0, 45.1, 32.7, 32.5, 28.7, 26.8, 25.6. MS (EI) m/z: [M]+
= 150.0.
9
of
a
yellow
oil.
(8E,10Z/8E,10E/8Z,10E/8Z,10Z
=
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90.5/4.5/3.5/1.5). GC: tR(8Z,10Z) = 8.90 min, tR(8E,10Z) = 8.99
min, tR(8Z,10E) = 9.03 min, tR(8E,10E) = 9.05 min. 1H NMR
(CDCl3, 400 MHz) δ 9.76 (t, J = 1.8 Hz, 1H, H1), 6.30 (ddd, J =
14.8, 10.8, 1.2 Hz, 1H, H9), 5.95 (dd, J = 10.9, 10.9 Hz, 1H, H10),
5.67 – 5.60 (m, 1H, H8), 5.29 (dt, J = 10.8, 7.6 Hz, 1H, H11), 2.42
(dt, J = 7.4, 1.8 Hz, 2H, H2), 2.16 – 2.06 (m, 4H, H7, H12), 1.67 –
1.58 (m, 2H, H3), 1.44 – 1.30 (m, 8H, H4, H5, H6, H13), 0.91 (t, J
= 7.4 Hz, 3H, H14). 13C NMR (CDCl3, 100 MHz) δ 203.0, 134.5,
130.2, 128.9, 126.0, 44.1, 32.9, 29.9, 29.3, 29.2, 29.1, 23.1, 22.2,
14.0. MS (EI) m/z: [M]+ = 208.2. All analytical data match those
previously reported by Grodner3 and Francke and coworkers4.
ASSOCIATED CONTENT
Grignard reagent 5 prepared from 7-chloroheptan-1-ol (4).
In a dry four-neck 2 L round-bottom flask equipped with a
mechanical stirrer, a thermometer, a condenser, and an argon inlet
were introduced magnesium (17 g, 697 mmol, 2.10 eq.) and THF
(63 mL). Ethyl bromide (1.5 g, 13.5 mmol, 0.04 eq.) was added
instantaneously under vigorous stirring and the reaction mixture
was then stirred at 50°C. A solution of n-butyl chloride (32.3 g, 349
mmol, 1.05 eq.) in THF (249 mL) was added dropwise in 2 h and,
after the end of the addition, the mixture was stirred 3 h under
reflux. The reaction mixture was cooled to -10°C and 7-
chloroheptan-1-ol 4 (50 g, 332 mmol, 1 eq.) was added dropwise in
30 min. The cooling bath was removed and the reaction mixture
was stirred for 30 min at 20°C then overnight under reflux. After
cooling to room temperature, the expected Grignard reagent
ClMgO(CH2)7MgCl 5 was obtained with a 90% yield.
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website. The SI PDF file contents H and 13C NMR
1
spectra of compounds discussed in this work, as well as Cartesian
coordinates and energetic features of DFT-calculated structures.
AUTHOR INFORMATION
Corresponding Author
* E-mail : guillaume.lefevre@chimieparistech.psl.eu
* E-mail : eric.gayon@m2i-development.com
The authors declare no competing financial interest.
(8E,10Z)-tetradeca-8,10-dien-1-ol (7). To 299 mmol (1.0 eq.)
of ClMgO(CH2)7MgCl prepared as described before were added
THF (402 mL) and, at -5°C, iron(III) acetylacetonate (106 mg, 0.30
mmol, 0.001 eq.) in one portion. To the dark mixture thus obtained,
diethyl ((1E,3Z)-hepta-1,3-dien-1-yl) phosphate 6a (83 g, 332
mmol, 1.1 eq.) was added dropwise in 50 min. The reaction mixture
was then stirred at 20°C overnight. The mixture was cooled to 5°C
and quenched adding progressively 500 mL of an aqueous solution
of HCl (2M). After decantation, the aqueous layer was extracted
with 3 x 250 mL of MTBE. The combined organic layers were
washed with 2 x500 mL of distilled water and concentrated under
vacuum. The resulting product was purified by chromatography on
a silica gel column using heptane/EtOAc 9:1 as eluent to obtain
56.0 g (89%) of an orange oil. (8E,10Z/8E,10E = 98.5/1.5). GC:
tR(8E,10Z) = 9.34 min, tR(8E, 10Z) = 9.39 min. 1H NMR (CDCl3,
400 MHz) δ 6.30 (ddd, J = 15.1, 11.0, 1.1 Hz, 1H), 5.96 (t, J = 10.9
Hz, 1H), 5.71 – 5.58 (m, 1H), 5.31 (dt, J = 10.7, 7.6 Hz, 1H), 3.64
(t, J = 6.6 Hz, 2H), 2.20 – 2.04 (m, 4H), 1.60 – 1.53 (m, 2H), 1.45
ACKNOWLEDGMENT
The M2i company is thanked for its financial support (CIFRE grant
program for P. C.) in the frame of the M2i-CNRS joint research
program “PheroChem”. Sophie Mendès, Daniel Guyot and Nicolas
Lefèvre (M2i company) are thanked for their contributions.
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